FC11 Streptococcal tonsillopharyngitis triggers psoriasis by inducing a cross-reactive autoimmune response between B cells and melanocytes

Abstract Psoriaiss is an HLA-C*06:02-associated T-cell-mediated autoimmune disease of the skin. Streptococcal tonsillopharyngitis caused by β-haemolytic streptococci is a common psoriasis trigger. The exact pathomechanism underlying the triggering event is unknown. We have investigated the relationship between streptococcal tonsillopharyngitis and psoriasis using a pathogenic Vα3S1/Vβ13S1 TCR that we had isolated from a lesional psoriatic CD8+ T-cell clone and expressed in a reporter mouse T-hybridoma cell line. With this TCR, we had previously shown that the major risk allele of psoriasis, HLA-C*06:02, mediates an autoimmune response of CD8+ T cells against melanocytes by presenting a melanocytic autoantigen as the pathomechanism underlying the HLA-association.1,2 We find in coculture experiments with cell suspensions from tonsils of HLA-C*06:02+ psoriasis patients who had undergone tonsillectomy for streptococcal-induced psoriasis that tonsillar B cells, as well as B cells from peripheral blood selectively activate the melanocyte-reactive Vα3S1/Vβ13S1 TCR in an IFN-γ-enhanced manner. B cells were further autostimulatory for CD8+ T cells from psoriasis patients. By matching the peptide recognition motif of the Vα3S1/Vβ13S1 TCR with the immunopeptidomes we had isolated from HLA-C*06:02 of B-cell lines homozygous for HLA-C*06:02 we identify several self-peptides that stimulate the Vα3S1/Vβ13S1 TCR as autoantigens. From the results of this unique approach for the identification of autoantigens in the immunopeptidome of a disease-mediating HLA-class I-molecule, we conclude that under the inflammatory conditions of streptococcal tonsillopharyngitis, B cells may stimulate potentially autoreactive CD8+ T cells that recognize different self-peptides presented by HLA-C*06:02 on B cells and melanocytes due to TCR polyspecificity. Streptococcal tonsillopharyngitis thus induces a cross-reactive autoimmune response between B cells in the tonsils and melanocytes in the skin that triggers psoriasis onset and relapses. These data call for a revision of the previous concept of molecular mimicry between streptococcal antigens and keratinocyte proteins as a pathomechanism of streptococci-induced psoriasis.